1. Field of the Invention
The present invention relates generally to the fields of disease prophylaxis and therapy. More particularly, it concerns agents that can bind to copper, in certain aspects forming a tripartite complex with protein, and the use of these agents in the prevention and treatment of diseases with a vascular component, such as cancer. Compositions and methods for combination therapy of these diseases, as well as therapeutic kits, are also provided.
2. Description of Related Art
Solid tumors require blood vessel proliferation (angiogenesis) for sustained growth in order to maintain adequate nutrition to other than the most peripheral cell layers (Hayes, 1994; Horak et al., 1993; Parangi et al., 1996). Normal adult human tissues, on the other hand, require little new blood vessel growth, except for wound repair, regeneration following trauma or surgery, and proliferation of the inner lining of the uterus during the menstrual cycle. Thus, dependency on angiogenesis is a fundamental difference between tumor and normal tissue. This difference is quantitatively more striking than the differences in cell replication and cell death rates, on which many cytoreductive chemotherapies depend. As a result of tumor dependency on angiogenesis, the concept of anti-angiogenic therapy for malignancies was developed (Folkman, 1995a; Folkman, 1995b; Hanahan and Folkman, 1996).
Copper is both a requirement and a potent stimulus for angiogenesis, as shown by studies of neovascularization in the rabbit cornea (Parke et al., 1988). During prostaglandin E1 (PGE1)-induced angiogenesis in the rabbit cornea, copper accumulates at the site where angiogenesis occurs (Parke et al., 1988). Conversely, in copper deficient rabbits, angiogenesis in the rabbit cornea in response to PGE1 is greatly reduced. In the rabbit cornea, copper for angiogenesis can be supplied by ceruloplasmin (a copper protein) as well as by dissolved copper sulfate, while apoceruloplasmin (ceruloplasmin without copper) does not support angiogenesis (Gullino, 1986). Additional studies have also shown that copper is an important angiogenic agent (Raju et al., 1982; Ziche et al., 1982). These studies all support the concept that unbound copper is required for angiogenesis.
Several years ago, some animal tumor model studies were carried out using an anti-copper approach (Brem et al., 1990a; 1990b; Yoshida et al., 1995). The chelator penicillamine plus a low-copper diet were used to lower copper levels in rats and rabbits with implanted intracerebral tumors. However, the animals treated with the low-copper regimen, while showing reduction in tumor size, did not show improved survival over untreated controls.
Penicillamine therapy has also been reported to be associated with significant side effects, including nausea and abdominal discomfort, and more serious side effects such as leukopenia and thrombocytopenia, which can lead to aplastic anemia. Nephrotic syndrome has also been reported in certain instances.
There are numerous other examples of diseases characterized by aberrant angiogenesis. One example of such a disease mediated by angiogenesis is ocular neovascular disease. This disease is characterized by invasion of new blood vessels into the structures of the eye such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age-related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch""s membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium.
Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis. The blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
There remains a need in the art for agents that effectively prevent, slow the onset or progression of, reduce or treat diseases characterized by angiogenesis, such as cancer, macular degeneration, and rheumatoid arthritis. The development of successful prophylactic or therapeutic agents that reduce the level of copper in vivo, without the side effects and risks associated with other copper reducing agents, would represent a particularly significant advance.
The present invention overcomes these and other deficiencies present in the art by providing methods and compositions that, in certain aspects of the invention, slow the onset or progression of or even prevent diseases characterized by aberrant vascularization or angiogenesis, such as cancer, and in other aspects of the invention, reduce or treat such diseases. This is accomplished by the provision of agents that reduce the level of copper in vivo, in preferred aspects through the formation of a tripartite agent-copper-protein complex. The compositions and methods of the present invention accomplish this without the side effects and risks associated with other copper reducing agents.
As used herein, the term xe2x80x9caberrant vascularizationxe2x80x9d or xe2x80x9caberrant angiogenesisxe2x80x9d will be understood to include abnormal neovascularization, including the formation of new blood vessels, larger blood vessels, more branched blood vessels (intussusception), and any and all mechanisms that lead to inappropriate or increased blood carrying capacity to a diseased tissue or site. The agents of the present invention will be understood to counteract xe2x80x9caberrant vascularizationxe2x80x9d or xe2x80x9caberrant angiogenesisxe2x80x9d, irrespective of the actual mechanism of action.
The present invention provides a method of delaying the onset of or preventing cancer in an animal, comprising administering to an animal at risk for developing cancer a biologically effective amount of at least a first pharmaceutical composition comprising at least a first prophylactic agent that binds copper and forms an agent-copper-protein complex upon administration to the animal. The protein in the agent-copper-protein complex can be a food protein, or a serum protein, such as serum albumin. The present invention also provides a method of delaying the onset of or preventing cancer in a human subject, comprising administering to a human subject at risk for developing cancer a biologically effective amount of at least a first pharmaceutical composition comprising at least a first prophylactic agent that binds copper and forms an agent-copper-protein complex upon administration to the human subject.
The present invention also provides a method of delaying the onset of or preventing cancer in an animal or human subject, comprising selecting an animal or human subject at risk for developing cancer, and administering to the animal or human subject at risk for developing cancer a therapeutically effective amount of at least a first pharmaceutical composition comprising at least a first prophylactic agent that binds copper and forms an agent-copper-protein complex upon administration to the animal or human subject. The xe2x80x9cselectingxe2x80x9d step may be accomplished, e.g., by identifying relatives of cancer patients and/or identifying susceptible subjects by genetic testing.
In certain aspects of the invention, the at least a first agent is a thiomolybdate compound. Preferred thiomolybdate compounds for use in the present invention include, but are not limited to, dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate or monothiomolybdate. In particularly preferred aspects of the invention, the at least a first agent is tetrathiomolybdate. In other embodiments of the invention, the thiomolybdate compound comprises at least a first iron atom and/or at least a first oxygen atom. It will be understood that complete oxidation of the thiomolybdate compound should preferably be avoided.
In other aspects of the invention, the thiomolybdate compound is associated with at least a first agent effective to form a stabilized thiomolybdate compound. Exemplary stabilizing agents are carbohydrate molecules, such as a monosaccharide, a disaccharide, a trisaccharide, an oligosaccharide or a polysaccharide. In preferred embodiments, the thiomolybdate compound is associated with at least a first sucrose molecule, such as forming a thiomolybdate compound associated with between about 5 and about 200 sucrose molecules, and in other preferred embodiments of the invention, the thiomolybdate compound is associated with about 30 sucrose molecules.
Thus, the present invention provides a method of delaying the onset of or preventing cancer in an animal, or in a human subject, comprising administering to the animal or subject a biologically effective amount of at least a first pharmaceutical composition comprising dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate, monothiomolybdate or a carbohydrate-associated complex thereof. The invention also provides a method of delaying the onset of or preventing cancer in an animal, or in a human subject, comprising administering to the animal or subject a biologically effective amount of a pharmaceutical composition comprising tetrathiomolybdate.
The agents for use in the present invention, such as tetrathiomolybdate, lower copper levels by forming a xe2x80x9ctripartite agent-copper-protein complexxe2x80x9d that is subsequently cleared from the body. The copper bound in these xe2x80x9ctripartite agent-copper-protein complexesxe2x80x9d is not reversibly released from these complexes, and are thus distinguished from reversible bipartite copper chelation.
As used herein, the term xe2x80x9cbiologically effective amountxe2x80x9d will be understood to mean an amount of an agent that binds copper and forms an agent-copper-protein complex effective to delay the onset of or prevent diseases associated with aberrant vascularization, preferably cancer, upon administration to selected animals or patients. Thus in the preventative aspects of the present invention, the term xe2x80x9cprophylactically effective amountxe2x80x9d can also be used to describe the amount of the instant compositions effective to delay the onset of or prevent diseases and/or cancer upon administration to selected animals or patients.
Alternatively, in the therapeutic aspects of the present invention, the term xe2x80x9ctherapeutically effective amountxe2x80x9d can also be used to describe the amount of the instant compositions effective to delay the onset of or prevent cancer. In terms of cancer treatment, amounts are effective to slow the growth of a tumor; to stop the growth of a tumor; to specifically induce necrosis in at least a portion of a tumor; and/or to induce tumor regression or remission upon administration to selected animals or patients. Such effects are achieved while exhibiting negligible or manageable adverse side effects on normal, healthy tissues of the animal or patient. Thus, the xe2x80x9ctherapeutically effective amountxe2x80x9d can vary from animal to animal or patient to patient, depending on a number of factors including, but not limited to, the extent of disease and the size of patient. All such dosing issues can be routinely addressed by the attending physician in light of the present disclosure.
The present invention further provides a method of treating an animal having at least a first tumor, comprising administering to the animal a biologically effective amount of at least a first pharmaceutical composition comprising at least a first agent that binds copper and forms an agent-copper-protein complex upon administration to the animal. Additionally, the present invention provides a method of treating a human patient having at least a first tumor, comprising administering to the patient a therapeutically effective amount of at least a first pharmaceutical composition comprising at least a first therapeutic agent that binds copper and forms an agent-copper-protein complex upon administration to the patient. In certain aspects of the invention, the at least a first agent is a thiomolybdate compound, such as dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate, monothiomolybdate or a carbohydrate-associated complex thereof. In particularly preferred embodiments of the invention, the at least a first agent is tetrathiomolybdate. Thus, the present invention provides a method of treating an animal or a human patient having at least a first tumor, comprising administering to the patient a therapeutically effective amount of dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate or monothiomolybdate. The present invention also provides a method of treating an animal or a human patient having at least a first tumor, comprising administering to the patient a therapeutically effective amount of tetrathiomolybdate. In various therapeutic embodiments of the present invention, the preferred at least a first agent is thus tetrathiomolybdate.
Thus, the present invention provides a method of prophylactic or therapeutic intervention in a human subject having or at risk for developing a tumor, comprising administering to the subject a prophylactically or therapeutically effective amount of at least a first agent that binds copper and forms an agent-copper-protein complex. The present invention further provides a method of prophylactic or therapeutic intervention in a human subject having or at risk for developing a tumor, comprising administering to the subject a prophylactically or therapeutically effective amount of dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate or monothiomolybdate. The present invention additionally provides a method of prophylactic or therapeutic intervention in a human subject having or at risk for developing a tumor, comprising administering to the subject a prophylactically or therapeutically effective amount of tetrathiomolybdate. The present invention also provides a method of treating a human patient having a tumor, preferably a vascularized tumor, comprising selecting a patient that would benefit from copper-protein complexation, and administering a therapeutically effective amount of at least a first copper-complexing agent effective to form agent-copper-protein complexes in the patient.
As used throughout the entire application, the terms xe2x80x9caxe2x80x9d and xe2x80x9canxe2x80x9d are used in the sense that they mean xe2x80x9cat least onexe2x80x9d, xe2x80x9cat least a firstxe2x80x9d, xe2x80x9cone or morexe2x80x9d or xe2x80x9ca pluralityxe2x80x9d of the referenced components or steps, except in instances wherein an upper limit is thereafter specifically stated. Therefore xe2x80x9can agent that binds copper and forms an agent-copper-protein complexxe2x80x9d means xe2x80x9cat least a first agent that binds copper and forms an agent-copper-protein complexxe2x80x9d. The operable limits and parameters of combinations, as with the amounts of any single agent, will be known to those of ordinary skill in the art in light of the present disclosure.
In certain aspects of the invention, the biologically effective amount of the at least a first agent is between about 20 mg and about 200 mg per patient. In certain aspects of the invention, the therapeutically effective amount of the at least a first agent is between about 20 mg and about 200 mg per patient over a therapeutically effective time or period. In general, the agent is administered to the patient daily, and thus in these embodiments of the invention, the biologically or therapeutically effective amount of the at least a first agent is between about 20 mg and about 200 mg per patient per day. xe2x80x9cBetween about 20 mg and about 200 mgxe2x80x9d includes all values in this range, and thus includes amounts of about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg or about 195 mg. xe2x80x9cAboutxe2x80x9d will be understood to include values above and below the given number. Thus, xe2x80x9cabout 20 mgxe2x80x9d will be understood to include about 18 mg, about 19 mg, about 21 mg and about 22 mg or so, and xe2x80x9cabout 200 mgxe2x80x9d will be understood to include about 201 mg, about 202 mg, about 203 mg and about 204 mg or so.
In other embodiments of the invention, the biologically or therapeutically effective amount of the at least a first agent is between about 20 mg and about 190 mg, between about 20 mg and about 180 mg, between about 20 mg and about 170 mg, between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 20 mg and about 110 mg, between about 20 mg and about 100 mg, between about 20 mg and about 90 mg, between about 20 mg and about 80 mg, between about 20 mg and about 70 mg, between about 20 mg and about 60 mg, between about 20 mg and about 50 mg, between about 20 mg and about 40 mg, between about 20 mg and about 30 mg, between about 30 mg and about 200 mg, between about 40 mg and about 200 mg, between about 50 mg and about 200 mg, between about 60 mg and about 200 mg, between about 70 mg and about 200 mg, between about 80 mg and about 200 mg, between about 90 mg and about 200 mg, between about 100 mg and about 200 mg, between about 10 mg and about 200 mg, between about 120 mg and about 200 mg, between about 130 mg and about 200 mg, between about 140 mg and about 200 mg, between about 150 mg and about 200 mg, between about 160 mg and about 200 mg, between about 170 mg and about 200 mg, between about 180 mg and about 200 mg, between about 190 mg and about 200 mg, between about 30 mg and about 190 mg, between about 40 mg and about 180 mg, between about 50 mg and about 170 mg, between about 60 mg and about 160 mg, between about 70 mg and about 150 mg, between about 80 mg and about 140 mg, between about 90 mg and about 130 mg, between about 100 mg and about 120 mg, between about 125 mg and about 200 mg or between about 150 mg and about 180 mg per patient per day.
These values can also be expressed in terms of mg/kg of body weight. As described above, the biologically or therapeutically effective amount can vary depending on the size of the animal or human patient. However, taking the average weight of a human male as about 70 kg, the biologically or therapeutically effective amount of the agent that binds copper and forms an agent-copper-protein complex for an average human male would be between about 0.3 mg/kg and about 3 mg/kg or so.
The compositions and methods of the present invention can be used to treat all forms of solid tumors having a vascular component, in particular those that are extensively vascularized, although this is not required in all aspects of the invention. Solid tumors, such as carcinomas and sarcomas, are exemplary of the types of tumors amenable to treatment with the instant compositions and methods. Particular examples of the types of tumors that may be prevented or treated using the present invention include, but are not limited to, renal, lung, breast, colon, prostate, stomach, liver, pancreas, esophagus, brain and larynx tumors, as well as angiosarcomas and chondrosarcomas.
Tumors of various sizes may also be treated using the present invention. Thus, small tumors, including metastatic tumors, exemplified by tumors that are about 1 cm in diameter or less, medium or moderate tumors, exemplified by tumors that are between about 1 cm and about 5 cm in diameter, and large tumors, exemplified by tumors that are about 5 cm in diameter or greater are contemplated for treatment using the present invention. In the context of the present invention, the term xe2x80x9ca vascularized tumorxe2x80x9d most preferably means a vascularized, malignant tumor, solid tumor or xe2x80x9ccancerxe2x80x9d.
Since, as discussed above, the instant compositions and methods are not completely specific to any particular tumor type, patients having more than one type of tumor may also be treated by the present invention. Thus, patients having at least a first and at least a second distinct type of tumor, exemplified by, but not limited to, a breast tumor and a chondrosarcoma or a renal tumor and a lung tumor, at least three distinct types of tumors, at least four distinct types of tumors, at least five distinct types of tumors or more are contemplated for treatment using the present invention.
In certain preferred aspects of the present invention, the at least a first agent is administered to the patient orally. However, other routes of administration are contemplated, including, but not limited to, intravenous, intramuscular and subcutaneous injections, slow release formulations and the like.
In certain embodiments of the invention, the methods further comprise administering to the human subject a therapeutically effective amount of at least a second anti-cancer agent. Exemplary of the additional anti-cancer agents contemplated for use are chemotherapeutic agents, radiotherapeutic agents, distinct copper chelating agents, anti-angiogenic agents, apoptosis-inducing agents or zinc compounds. In further aspects of the present invention, the methods further comprise subjecting the patient to surgery or radiotherapy.
The at least a first anti-cancer agent may be a xe2x80x9cchemotherapeutic agentxe2x80x9d. As used herein, the term xe2x80x9cchemotherapeutic agentxe2x80x9d is used to refer to a classical chemotherapeutic agent or drug used in the treatment of malignancies. This term is used for simplicity notwithstanding the fact that other compounds, including immunotoxins, may be technically described as a chemotherapeutic agent in that they exert an anti-cancer effect. However, xe2x80x9cchemotherapeuticxe2x80x9d has come to have a distinct meaning in the art and is being used according to this standard meaning. xe2x80x9cChemotherapeuticsxe2x80x9d in the context of the present application therefore do not generally refer to immunotoxins, radiotherapeutic agents and such like, despite their operational overlap.
A number of exemplary chemotherapeutic agents are listed in Table 1. Those of ordinary skill in the art will readily understand the uses and appropriate doses of chemotherapeutic agents, although the doses may well be reduced when used in combination with the present invention. A new class of drugs that may also be termed xe2x80x9cchemotherapeutic agentsxe2x80x9d are agents that induce apoptosis. Any one or more of such drugs, including genes, vectors and antisense constructs, as appropriate, may also be used in conjunction with the present invention.
In certain aspects of the present invention, the methods comprise administering a therapeutically effective amount of a zinc compound to the animal or human subject. In preferred embodiments, the methods comprise administering the at least a first agent to the animal or human subject in an amount and for a time effective to reduce the level of copper in the animal or human subject to about 20% of the level of copper in the animal or human subject prior to administration of the at least a first agent, and administering to the animal or human subject a therapeutically effective amount of a zinc compound, such as zinc acetate. In yet other preferred aspects, the therapeutically effective amount of a zinc compound is administered to the animal or human subject for a period of time effective to maintain the level of copper in the animal or human subject at about 20% of the level of copper in the animal or human subject prior to administration of the at least a first agent.
The present invention also provides methods of treating cancer in a human subject, comprising administering a pharmaceutical composition comprising tetrathiomolybdate to a human subject having cancer in an amount and for a time effective to reduce the level of copper in the human subject to about 20% of the level of copper in the human subject prior to administration of tetrathiomolybdate, and administering to the human subject a pharmaceutical composition comprising a therapeutically effective amount of a zinc compound.
The present invention also provides methods of treating or preventing a disease characterized by aberrant vascularization in an animal or a human patient, comprising administering to an animal or a human patient having or at risk for developing a disease characterized by aberrant vascularization a therapeutically effective amount of at least a first pharmaceutical composition comprising at least a first agent that binds copper and forms an agent-copper-protein complex. In preferred embodiments of the invention, the disease is cancer, wet type macular degeneration or rheumatoid arthritis.
Further provided by the present invention are methods of treating or preventing wet type macular degeneration in an animal or human patient, comprising administering to an animal or human patient having or at risk for developing wet type macular degeneration a therapeutically effective amount of at least a first pharmaceutical composition comprising at least a first agent that binds copper and forms an agent-copper-protein complex. In certain aspects of the invention, the at least a first agent is a thiomolybdate compound, such as dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate, monothiomolybdate, or a carbohydrate-associated complex of any of the foregoing.
Additionally, the present invention provides methods of treating or preventing rheumatoid arthritis in an animal or human patient, comprising administering to an animal or human patient having or at risk for developing rheumatoid arthritis a therapeutically effective amount of at least a first pharmaceutical composition comprising at least a first agent that binds copper and forms an agent-copper-protein complex. In preferred aspects of the invention, the at least a first agent is a thiomolybdate compound, such as dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate, monothiomolybdate, or a carbohydrate-associated complex of any of the foregoing.
The present invention also provides a composition, or a pharmaceutical composition, comprising a combined therapeutic amount of at least a first agent that binds copper and forms an agent-copper-protein complex and at least a second anti-cancer agent. In certain aspects of the invention, the at least a first agent is a thiomolybdate compound, such as dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate, monothiomolybdate, or a carbohydrate-associated complex thereof. In preferred aspects of the invention, the at least a first agent that binds copper and forms an agent-copper-protein complex is tetrathiomolybdate. In further preferred embodiments, the at least a second anti-cancer agent is a chemotherapeutic agent, a radiotherapeutic agent, a distinct copper chelating agent, an anti-angiogenic agent, an apoptosis-inducing agent or a zinc compound. Thus, the present invention also provides a composition comprising a combined therapeutic amount of dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate or monothiomolybdate and at least a second anti-cancer agent. The present invention additionally provides a composition comprising a combined therapeutic amount of tetrathiomolybdate and at least a second anti-cancer agent. Pharmaceutical compositions comprising a thiomolybdate compound associated with at least a first carbohydrate molecule are also provided.
Also provided is a therapeutic kit comprising, in at least a first suitable container, a therapeutically effective combined amount of at least a first agent that binds copper and forms an agent-copper-protein complex, and at least a second anti-cancer agent. In certain aspects of the invention, the at least a first agent is a thiomolybdate compound, such as dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate or monothiomolybdate. In a preferred embodiment of the therapeutic kits of the present invention, the at least a first agent that binds copper and forms an agent-copper-protein complex is tetrathiomolybdate. In other aspects of the invention, the thiomolybdate compound is associated with at least a first carbohydrate molecule. In additional aspects of the therapeutic kits of the invention, the at least a second anti-cancer agent is a chemotherapeutic agent, a radiotherapeutic agent, a distinct copper chelating agent, an anti-angiogenic agent, an apoptosis-inducing agent or a zinc compound. In particular embodiments of the present invention, the at least a first agent that binds copper and forms an agent-copper-protein complex and the at least a second anti-cancer agent are comprised in at least a first and at least a second separate containers.
The present invention also provides therapeutic kits comprising, in at least a first suitable container, a therapeutically effective combined amount of dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate, monothiomolybdate, or a carbohydrate-associated complex thereof, and at least a second anti-cancer agent. Further provided are therapeutic kits comprising, in at least a first suitable container, a therapeutically effective combined amount of tetrathiomolybdate and at least a second anti-cancer agent.
The present invention additionally provides compositions comprising a thiomolybdate compound associated with at least a first stabilizing molecule, such as a carbohydrate molecule, or a xe2x80x9cthiomolybdate-carbohydrate complexxe2x80x9d. In certain aspects of the invention, the thiomolybdate compound comprises at least a first iron residue and/or at least a first oxygen residue. In other aspects, the ratio of carbohydrate molecules, or sugar units, to the thiomolybdate compound is between about 200 to 1 and about 5 to 1. It will be understood that all ratios within this range are also included, such as ratios of about 190 to 1, about 180 to 1, about 175 to 1, about 170 to 1, about 160 to 1, about 150 to 1, about 140 to 1, about 130 to 1, about 125 to 1, about 120 to 1, about 110 to 1, about 100 to 1, about 90 to 1, about 80 to 1, about 75 to 1, about 70 to 1, about 60 to 1, about 50 to 1, about 40 to 1, about 30 to 1, about 25 to 1, about 20 to 1, about 15 to 1 and about 10 to 1. In preferred aspects of the invention, the ratio of carbohydrate molecules to the thiomolybdate compound is about 30 to 1.
In further embodiments of the present invention, the at least a first carbohydrate molecule is a monosaccharide. In other aspects, the at least a first carbohydrate molecule is a disaccharide, such as sucrose. In yet other aspects, the at least a first carbohydrate molecule is an oligosaccharide. In certain embodiments, the thiomolybdate compound is associated with at least a first and at least a second distinct carbohydrate molecule.
The thiomolybdate compound may be non-covalently bonded to the at least a first stabilizing agent, e.g., carbohydrate molecule, such as by hydrogen bonding. In other aspects of the invention, the thiomolybdate compound is covalently bonded to at least a first stabilizing agent, e.g., carbohydrate molecule. In still other aspects, the thiomolybdate compound is complexed with the at least a first carbohydrate molecule. In preferred aspects, the thiomolybdate compound is dodecathiodimolybdate, tetrathiomolybdate, iron octathiodimolybdate, trithiomolybdate, dithiomolybdate or monothiomolybdate. In particularly preferred aspects, the thiomolybdate compound is tetrathiomolybdate. In further aspects, the compositions comprises a zinc compound. In other preferred aspects, the composition is dispersed in a pharmaceutically acceptable excipient. The present invention thus provides stabilized tetrathiomolybdate compositions comprising tetrathiomolybdate associated with about 30 sucrose molecules.
The agents that bind copper and form an agent-copper-protein complex, as described herein, can be used in treating or preventing a disease characterized by aberrant vascularization, including, but not limited to, cancer, wet type macular degeneration or rheumatoid arthritis. Use of the agents that binds copper and forms an agent-copper-protein complex in the manufacture of medicaments for treating or preventing a disease characterized by aberrant vascularization, including, but not limited to, cancer, wet type macular degeneration or rheumatoid arthritis, are thus also provided.